Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• Phosphoinositide-3-kinases play a variety of roles in normal tissue physiology, with pl 10a having a specific role in cancer growth, pl 10b in thrombus formation mediated by integrin a p b3, and pl 10g, in inflammation, rheumatoid arthritis, and other chronic inflammation states.
• Inhibitors of PI3K have therapeutic potential in the treatment of various proliferative diseases, including cancer.
• Some embodiments provided herein describe a method of treating cancer, comprising administering to a subject in need thereof a single pharmaceutical composition consisting of:
• X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are
• R x is hydrogen or Ci_ 6 alkyl
• R 1 and R 2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ 6 alkyl, C 2-f alkenyl, C 2-f alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -
• each R la , R lb , R lc , and R ld is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-f alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R lb and R lc together with the N atom to which they are attached form heterocyclyl;
• R 3 and R 4 are each independently hydrogen or Ci_ 6 alkyl; or R 3 and R 4 are linked together to form a bond, Ci_ 6 alkylene, Ci_ 6 heteroalkylene, C 2-6 alkenylene, or C 2-6 heteroalkenylene;
• R 5a is (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5
• R 5b is (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl,
• R 5C is -(CR 5f R 5g ) ceremoni-(C 6 _i 4 aryl) or -(CR 5f R 5g ) ceremoni-heteroaryl;
• R 5d and R 5e are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
• R 5f and R 5g are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl,
• R 6 is hydrogen, Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -S(0)-Ci_ 6 alkyl, or -S0 2 -Ci_ 6 alkyl;
• n 0 or 1 ;
• n 0, 1, 2, 3, or 4; wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R 1 , R 2 , R 3 , R 4 , R 6 , R x , R la , R lb , R lc , R ld , R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , and R 5g is optionally substituted with one, two, three, or four substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl
• each R a , R b , R c , and R d is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one, two, three, or four substituents Q a ;
• each Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)R e , -C(0)0R e , -C(0)NR f R g , -C(NR e )NR f R g , -OR e , -0C(0)R e , -
• each R e , R f , R g , and R h is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl; and
• a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject daily.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject once per day, twice per day, or three times per day.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject once per day.
• about 60 mg/day of the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject on a 28 -day cycle.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject for at least one 28 -day cycle.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject for at least two 28-day cycles.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject for a period of up to about 7 days.
• the days over which the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof are intermittent.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for about 7 consecutive days in a 28 -day cycle.
• the method comprises an intermittent dosing schedule (IS), comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for 7 consecutive days followed by 21 days without treatment in a 28-day cycle.
• IS intermittent dosing schedule
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject until disease progression or intolerable toxicity.
• the method comprises a continuous daily dosing schedule (CS), comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for 28 consecutive days in a 28 -day cycle.
• CS continuous daily dosing schedule
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject for at least two CS 28-day cycles.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject once weekly after the at least two CS 28-day cycles until disease progression or intolerable toxicity.
• the method further comprising an IS, comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for 7 consecutive days followed by 21 days without treatment in a 28-day cycle after the at least two CS 28-day cycles.
• X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are
• R x is hydrogen or Ci_ 6 alkyl
• R 1 and R 2 are each independently (a) hydrogen, cyano, halo, or nitro
• Ci_ 6 alkyl, C 24 alkenyl, C 24 , alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl
• -C(0)R la , -
• each R la , R lb , R lc , and R ld is independently (i) hydrogen;
• Ci_ 6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R lb and R lc together with the N atom to which they are attached form heterocyclyl;
• R 3 and R 4 are each independently hydrogen or Ci_ 6 alkyl; or R 3 and R 4 are linked together to form a bond, Ci- 6 alkylene, Ci_ 6 heteroalkylene, C 2-6 alkenylene, or C 2-6 heteroalkenylene;
• R 5a is (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl,
• R 5b is (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl,
• R 5C is -(CR 5f R 5g ) n -(C 6-14 aryl) or -(CR 5f R 5g ) n -heteroaryl;
• R 5d and R 5e are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
• R 5f and R 5g are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , - C(0)NR lb R lc , -C(NR la )NR lb R lc , -OR la , -0C(0)R la , -0C(0)0R la , -0C(0)NR lb R lc , -OR la , -0C(0)R la , -0C(0)0R la , -0C(0)NR lb R lc , -
• R 6 is hydrogen, Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -S(0)-Ci_ 6 alkyl, or -S0 2 -Ci_ 6 alkyl;
• n 0 or 1 ;
• n 0, 1, 2, 3, or 4;
• each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R 1 , R 2 , R 3 , R 4 , R 6 , R x , R la , R lb , R lc , R ld , R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , and R 5g is optionally substituted with one, two, three, or four substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aral
• R c , and R d is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _ i4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one, two, three, or four substituents Q a ;
• each Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro;
• Ci_ 6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)R e , -C(0)0R e , -C(0)NR f R g , -C(NR e )NR f R g , -OR e , -0C(0)R e , -
• each R e , R f , R g , and R h is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _io cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are atached form heterocyclyl;
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject once daily for a period of about 7 days in a 28 -day cycle.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for about 7 consecutive days in a 28 -day cycle.
• the method comprises an intermittent dosing schedule (IS), comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for 7 consecutive days followed by 21 days without treatment in a 28-day cycle.
• IS intermittent dosing schedule
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for at least one 28-day cycle.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for at least three 28-day cycles,
• the first two 28-day cycles comprise a continuous daily dosing schedule (CS), comprising
• the third 28-day cycle comprises an intermittent dosing schedule (IS), comprising administering to the subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, once daily for only the first 7 consecutive days of the 28-day cycle.
• IS intermittent dosing schedule
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject for at least three cycles,
• the first two cycles comprise a continuous daily dosing schedule (CS), comprising administering to the subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for two cycles; and
• CS continuous daily dosing schedule
• the subsequent cycle(s) comprises an intermittent dosing schedule (IS), comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for only the first 7 consecutive days in each subsequent cycle.
• IS intermittent dosing schedule
• X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are
• R x is hydrogen or Ci_ 6 alkyl
• R 1 and R 2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ 6 alkyl, C 24 , alkenyl, C 24 , alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -
• each R la , R lb , R lc , and R ld is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R lb and R lc together with the N atom to which they are attached form heterocyclyl;
• R 3 and R 4 are each independently hydrogen or Ci_ 6 alkyl; or R 3 and R 4 are linked together to form a bond, Ci_ 6 alkylene, Ci_ 6 heteroalkylene, C 2-6 alkenylene, or C 2-6 heteroalkenylene;
• R 5a is (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl,
• R 5b is (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl,
• R 5C is -(CR 5f R 5g ) n -(C 6.14 aryl) or -(CR 5f R 5g ) n -heteroaryl;
• R 5d and R 5e are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
• R 5f and R 5g are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
• R 6 is hydrogen, Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -S(0)-Ci_ 6 alkyl, or -S0 2 -Ci_ 6 alkyl;
• n 0 or 1 ;
• n 0, 1, 2, 3, or 4;
• each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R 1 , R 2 , R 3 , R 4 , R 6 , R x , R la , R lb , R lc , R ld , R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , and R 5g is optionally substituted with one, two, three, or four substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aral
• R c , and R d is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _ i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one, two, three, or four substituents Q a ;wherein each Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4
• each R e , R f , R g , and R h is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl, wherein the method comprises at least three 28-day cycles,
• the first two cycles comprise a continuous daily dosing schedule (CS), comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for 28 consecutive days in a 28-day cycle; and
• CS continuous daily dosing schedule
• the third and subsequent cycles comprise an intermittent dosing schedule (IS), comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for 7 consecutive days followed by 21 days without treatment in a 28-day cycle.
• IS intermittent dosing schedule
• the IS is continued until progression of disease.
• progression of disease is observed, the subject resumes CS.
• the CS is continued until unacceptable toxicity.
• T-cells are recovered and/or re -populated during the 21 days without treatment.
• regulatory T-cells and/or effector T-cells are recovered and/or re-populated during the 21 days without treatment.
• the incidence of at least one toxicity is reduced.
• the at least one toxicity is enterocolitis, a cutaneous toxicity, liver toxicity, pulmonary toxicity, infection, or any combination thereof.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject on an intermittent dosing schedule (IS) until disease progression occurs.
• IS intermittent dosing schedule
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered daily to the subject on a continuous dosing schedule (CS) after disease progression occurs on an intermittent dosing schedule (IS).
• CS continuous dosing schedule
• IS intermittent dosing schedule
• the cancer is acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, myelodysplastic syndrome, refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, preleukemia, chronic myelomonocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera,
• Hodgkin's disease non-Hodgkin's disease, multiple myeloma, Waldenstrom's macroglobulinemia;
• monoclonal gammopathy of undetermined significance benign monoclonal gammopathy, heavy chain disease, bone and connective tissue sarcoma, brain tumor, breast cancer, adrenal cancer, thyroid cancer, pancreatic cancer, pituitary cancer, eye cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, hepatocellular carcinoma, hepatoblastoma, gallbladder cancer, adenocarcinoma, cholangiocarcinoma, lung cancer, testicular cancer, prostate cancer, penal cancer; oral cancer, basal cancer, salivary gland cancer, pharynx cancer, skin cancer, kidney cancer, bladder cancer, myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangio-endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epi
• the cancer is leukemia, lymphoma, multiple myeloma, sarcoma, a brain tumor, breast cancer, adrenal cancer, thyroid cancer, pancreatic cancer, pituitary cancer, cervical cancer, ovarian cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, lung cancer, testicular cancer, prostate cancer, or skin cancer.
• the cancer is the cancer is acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic myelomonocytic leukemia (CMML), chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia,
• CMML chronic myelomonocytic leukemia
• granulocytic leukemia chronic lymphocytic leukemia
• hairy cell leukemia hairy cell leukemia
• the cancer is chronic lymphocytic leukemia or non-Hodgkin’s lymphoma.
• the cancer is a hematological cancer or malignancy.
• the cancer is a B-cell malignancy.
• the cancer is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), high-risk chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B- cell lymphoma (PMBL), immunoblastic large
• the cancer is non-Hodgkin’s lymphoma diffuse large B-cell lymphoma (DLBCL).
• DLBCL diffuse large B-cell lymphoma
• the cancer is relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL).
• the diffuse large B-cell lymphoma is of the activated B-cell (ABC DLBCL) or Germinal center B-cell (GCB DLBCL).
• the cancer is follicular lymphoma (FL).
• the FL is relapsed/refractory FL.
• the FL is relapsed/refractory FL after failure of at least two prior lines of systemic therapy in the subject.
• the FL is relapsed/refractory FL after failure of at least two prior lines of systemic therapy in the subject, wherein the systemic therapy comprises an antiCD20 antibody and/or chemotherapy with an alkylating agent or a purine analog.
• follicular lymphoma FL
• methods of treating follicular lymphoma (FL) in a subject in need thereof, wherein the subject has failed two or more prior chemotherapies In some embodiments provided herein are methods of treating follicular lymphoma (FL) in a subject in need thereof, wherein the subject has failed two or more prior systemic chemotherapies. In some embodiments provided herein are methods of treating follicular lymphoma (FL) in a subject in need thereof, wherein the subject has failed two or more prior systemic chemotherapies, wherein each systemic chemotherapy is selected from the group consisting of an antiCD20 antibody, an alkylating chemotherapeutic agent, and a chemotherapeutic purine analog. [0046] In another aspect herein is provided a method of treating follicular lymphoma (FL), comprising administering to a subject in need thereof a single pharmaceutical composition consisting of:
• X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are
• R x is hydrogen or Ci_ 6 alkyl
• R 1 and R 2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ 6 alkyl, C 24 , alkenyl, C 24 , alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -
• each R la , R lb , R lc , and R ld is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R lb and R lc together with the N atom to which they are attached form heterocyclyl;
• R 3 and R 4 are each independently hydrogen or Ci_ 6 alkyl; or R 3 and R 4 are linked together to form a bond, Ci_ 6 alkylene, Ci_ 6 heteroalkylene, C 2-6 alkenylene, or C 2-6 heteroalkenylene;
• R 5a is (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5
• R 5b is (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl,
• R 5C is -(CR 5f R 5g ) n -(C 6.14 aryl) or -(CR 5f R 5g ) n -heteroaryl;
• R 5d and R 5e are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl,
• R 5f and R 5g are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
• R 6 is hydrogen, Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -S(0)-Ci_ 6 alkyl, or -S0 2 -Ci_ 6 alkyl;
• n 0 or 1 ;
• n 0, 1, 2, 3, or 4;
• each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R 1 , R 2 , R 3 , R 4 , R 6 , R x , R la , R lb , R lc , R ld , R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , and R 5g is optionally substituted with one, two, three, or four substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aral
• R c , and R d is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _ i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one, two, three, or four substituents Q a ;wherein each Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 24 , alkenyl, C 2-f alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4
• each R e , R f , R g , and R h is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl.
• R 5b is (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, or heteroaryl; or (c) -C(0)R la , -C(0)0R la , -
• R 5a and R 5b are each independently (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or
• R 5a and R 5b are each methyl, optionally substituted with one, two, or three halo(s).
• n 1
• R 5f and R 5g are each hydrogen.
• n 0.
• m is 0.
• the compound of Formula (I) is of Formula
• R 7c , R 7d , and R 7e are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ; or (c) -C(0)R a , -
• R 7a , R 7b , R 7c , R 7d , and R 7e that are adjacent to each other form C 3 _i 0 cycloalkenyl, C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one, two, three, or four substituents Q a .
• X, Y, and Z are each N;
• R 1 and R 2 are each hydrogen
• R 3 and R 4 are each hydrogen
• R 5a is Ci_ 6 alkyl
• R 5b is Ci_ 6 alkyl
• R 5C is -(CH 2 )-phenyl, wherein R 5c is optionally substituted with one, two, three, or four substituents Q;
• R 5d and R 5e are each hydrogen
• R 6 is CHF 2 ;
• n 0;
• each alkyl is optionally substituted with one, two, three, or four substituents Q, wherein each substituent Q is independently selected from C 6 _i 4 aryl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a , wherein the heteroaryl has from 5 to 10 ring atoms and one or more heteroatoms independently selected from O, S, and N, and the heterocyclyl has from 3 to 15 ring atoms and one or more heteroatoms independently selected from O, S, and N;
• each Q a is independently selected from the group consisting of halo, Ci_ 6 alkyl, Ci_ 6 alkylsulfonyl and -OR e , wherein R e is hydrogen or Ci_ 6 alkyl.
• R 5a and R 5b are each methyl, optionally substituted with one or more halos.
• the compound of Formula (I) is Compound A35:
• the compound of Formula (I) is Compound
• the compound of Formula (I) is Compound
• the compound of Formula (I) is Compound
• the compound of Formula (I) is Compound A37:
• the compound of Formula (I) is Compound A38:
• the compound of Formula (I) is Compound
• the compound of Formula (I) is Compound A42:
• the compound of Formula (I) is Compound A43:
• the compound of Formula (I) is Compound A44:
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject orally.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is formulated as a tablet or capsule.
• FIGS. 1A-1B Schematic representations of dosing schedules: A depicts the Continuous Schedule (CS); and B depicts the Intermittent Schedule (IS).
• FIG.2 Graphical representation showing the best change from baseline of measurable lesions for monotherapy with Compound A35 on a continuous dosing schedule (CS) or intermittent dosing schedule (IS) in follicular lymphoma patients.
• CS continuous dosing schedule
• IS intermittent dosing schedule
• FIG.3 Graphical representation showing preferential tumor exposure of Compound A35 over a 4-hour and 24-hour period.
• FIG.4 Graphical representation showing preferential retention of Compound A35 compared to idelalisib in murine B-cell tumors.
• FIG.5 Schematic representation of monotherapy treatment paradigm with Compound A35 in patients with R/R FL.
• FIGS. 6A-6B Graphical representation of Intermittent Dosing Schedule with Compound A35 (A) compared to parsaclisib (B) to maintain disease control.
• compositions comprising a PI3K delta inhibitor and methods for treating patients with B cell malignancies with a PI3K inhbitor.
• the dosing regimens and schedules described herein reduce toxicities associate with PI3K delta inhibitors.
• PI3Ks Class I phosphatidylinositol 3-kinases
• PI3Ks are composed of regulatory (p85) and catalytic (pl 10) subunits, with the catalytic unit consisting of 4 distinct isoforms designated a, b, g, and d.
• PI3K5 is primarily expressed in lymphocytes where it plays a key role in normal lymphocyte biology including proliferation, homing and survival.
• RI3Kd is frequently active in B-cell malignancies and is central to multiple B-cell receptor (BCR) signaling pathways that drive proliferation, survival, homing and retention of malignant B-cells in lymphoid tissue and bone marrow.
• BCR B-cell receptor
• Small molecule PI3K delta (or RI3Kd) inhibitors are effective for the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL) , follicular lymphoma and other B- cell lymphomas.
• CLL chronic lymphocytic leukemia
• follicular lymphoma follicular lymphoma
• other B- cell lymphomas e.g., B-cell malignancies
• toxicities associated with the RI3Kd are severe and have been fatal in some patients.
• Toxicities reported with RI3Kd inhibitors include but are not limited to enterocolitis (manifested as diarrhea/colitis), cutaneous toxicities (e.g., rashes), liver toxicity (manifested as elevation of transaminases), pulmonary toxicity (manifested as non-infectious pneumonitis), and infections. These toxicities may be severe and have been fatal in some patients. The frequency, severity and time to onset of these adverse events (AEs) vary among RI3Kd inhibitors.
• enterocolitis manifested as diarrhea/colitis
• cutaneous toxicities e.g., rashes
• liver toxicity manifested as elevation of transaminases
• pulmonary toxicity manifested as non-infectious pneumonitis
• AEs adverse events
• lymphocytic infiltrates have reported in biopsies obtained from subjects with colitis and/or severe skin rash with corticosteroid therapy being an effective treatment approach in patients who developed diarrhea and rash.
• T lymphocytes have been shown to have an important role in controlling auto-immunity.
• pl 10d was shown to be required for mounting and effective T-cell responses to viral and bacterial infections.
• RI3Kd inhibition results in various immune-mediated toxicities such as enterocolitis and skin toxicity due to TREG suppression, as well as infections due to suppression of B-cells and effector T-cells.
• treatment regimens with small molecule PI3K5 delta (or PI3K5) inhibitors on an intermittent dosing schedule are used.
• progression of disease is observed in subjects who are treated for B-cell malignancies, including chronic lymphocytic leukemia (CLL) and lymphomas with small molecule PI3K5 inhibitors (e.g., parsaclisib (INCB050465)) on an IS dosing regimen (see FIG. 6B). It has been demonstrated that parsaclisib once weekly dosing resulted in plasma levels > IC 90 for 1.5/7 days (i.e., 32%).
• the methods of treatment and dosing regimens and schedules described herein provide an efficacious and tolerable treatment of cancer. In some embodiments, the methods of treatment and dosing regimens and schedules described herein improve the frequency, severity and time to onset of the adverse events (AEs) associated with PI3K delta inhibitors. In some embodiments, the methods of treatment and dosing regimens and schedules described herein, including IS dosing regimens, result in partial or complete remission.
• AEs adverse events
• the methods of treatment and dosing regimens and schedules described herein including IS dosing regimens (e.g., one week on / three week off dosing), result in plasma levels of > IC 90 for 9/28 days (i.e., 32%) for the compounds described herein.
• plasma levels underestimate tissue levels, and higher levels of the compounds described herein are predicted in tumor versus plasma (FIG. 6A).
• the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
• the term“subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
• the terms“subject” and“patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.
• the terms“treat,”“treating,” and“treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
• the terms“prevent,”“preventing,” and“prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.
• the terms“therapeutically effective amount” or“effective amount” are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
• the terms “therapeutically effective amount” or“effective amount” also refer to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
• each component is“pharmaceutically acceptable” in the sense of being compatible with other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically-acceptable material such as a liquid or solid filler, diluent, solvent, or encapsulating material.
• each component is“pharmaceutically acceptable” in the sense of being compatible with other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice of Pharmacy, 2lst Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and
• the term“about” or“approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term“about” or“approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term“about” or“approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
• active ingredient and“active substance” refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition.
• active ingredient and“active substance” may be an optically active isomer of a compound described herein.
• the terms“drug,”“therapeutic agent,” and“chemotherapeutic agent” refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition.
• the term“PI3K” refers to a phosphoinositide 3-kinase or variant thereof, which is capable of phosphorylating the inositol ring of PI in the D-3 position.
• the term“PI3K variant” is intended to include proteins substantially homologous to a native PI3K, i.e., proteins having one or more naturally or non- naturally occurring amino acid deletions, insertions, or substitutions (e.g., PI3K derivatives, homologs, and fragments), as compared to the amino acid sequence of a native PI3K.
• the amino acid sequence of a PI3K variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native PI3K.
• PI3K examples include, but are not limited to, pl 10a, pl 10b, pl 105, pl 10g, PI3K-C2a, PI3K-C2P, PI3K-C2y, Vps34, mTOR, ATM, ATR, and DNA-PK. See, Fry, Biochem. Biophys. Acta 1994, 1226 , 237-268; Vanhaesebroeck and Waterfield, Exp. Cell. Res. 1999, 253, 239-254; and Fry, Breast Cancer Res. 2001, 3, 304-312. PI3Ks are classified into at least four classes. Class I includes pl 10a, pl lOp, pl 105, and pl 10g.
• Class II includes PI3K-C2a, PI3K-C2P, and PI3K-C2y.
• Class III includes Vps34.
• Class IV includes mTOR, ATM, ATR, and DNA-PK.
• the PI3K is a Class I kinase.
• the PI3K is pl 10a, pl lOp, pl 105, or pl lOy.
• the PI3K is PI3K delta.
• the PI3K is a variant of a Class I kinase.
• the PI3K is a pl 10a mutant.
• pl 10a mutants include, but are not limited to, R38H, G106V, K111N, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K,
• the PI3K is a Class II kinase.
• the PI3K is PI3K-C2a, PI3K- C2p, or PI3K-C2y.
• the PI3K is a Class III kinase.
• the PI3K is Vps34.
• the PI3K is a Class IV kinase.
• the PI3K is mTOR, ATM, ATR, or DNA-PK.
• an“isotopic variant” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound.
• an“isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( ' H).
• an“isotopic variant” of a compound is in a stable form, that is, non radioactive. In certain embodiments, an“isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 'H).
• an“isotopic variant” of a compound is in an unstable form, that is, radioactive.
• an“isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( H), carbon-l 1 ( C), carbon-l4 ( C), nitrogen-l3 ( N), oxygen-l4 ( 14 0), oxygen-l5 ( 15 0), fluorine-l8 ( 18 F), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-35 ( 35 S), chlorine-36 ( 36 Cl), iodine-l23 ( 123 I), iodine-l25 ( 125 I), iodine-l29 ( 129 I), and iodine-l3 l ( 131 I).
• any hydrogen can be 2 H, for example, or any carbon can be 13 C, for example, or any nitrogen can be 15 N, for example, or any oxygen can be 18 0, for example, where feasible according to the judgment of one of skill.
• an“isotopic variant” of a compound contains unnatural proportions of deuterium (D).
• alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkylene may optionally be substituted with one or more substituents Q as described herein.
• alkyl also encompasses both linear and branched alkyl, unless otherwise specified.
• the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (Ci -2 o), 1 to 15 (C 1-15), 1 to 10 (Ci_io), or 1 to 6 (C m, ⁇ ,) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C 3-2 o), 3 to 15 (C 3 _i 5 ), 3 to 10 (C 3 _i 0 ), or 3 to 6 (C 3-6 ) carbon atoms.
• linear Ci_ 6 and branched C 3-6 alkyl groups are also referred as“lower alkyl.”
• alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), «-propyl, isopropyl, butyl (including all isomeric forms), «-butyl, isobutyl, .vec-butyl. /-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).
• Ci_ 6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
• alkylene refers to a linear or branched saturated divalent hydrocarbon radical, wherein the alkylene may optionally be substituted with one or more substituents Q as described herein.
• alkylene encompasses both linear and branched alkylene, unless otherwise specified.
• the alkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (Ci_ 2 o), 1 to 15 (C 1-15), 1 to 10 (C 1-10 ), or 1 to 6 (C m, ⁇ ,) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3 _i 5 ), 3 to 10 (C 3 _i 0 ), or 3 to 6 (C 3-6 ) carbon atoms.
• linear Ci_ 6 and branched C 3-6 alkylene groups are also referred as“lower alkylene.”
• alkylene groups include, but are not limited to, methylene, ethylene, propylene (including all isomeric forms), «- propylene, isopropylene, butylene (including all isomeric forms), «-butylene, isobutylene, /-butylene, pentylene (including all isomeric forms), and hexylene (including all isomeric forms).
• Ci_ 6 alkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
• heteroalkylene refers to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms each independently selected from O, S, and N in the hydrocarbon chain.
• Ci_ 6 heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
• the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (Ci_ 20 ),
• linear Ci_ 6 and branched C 3-6 heteroalkylene groups are also referred as“lower heteroalkylene.”
• heteroalkylene groups include, but are not limited to, -CH 2 0-, -CH 2 OCH 2 -, -CH 2 CH 2 0-, -CH 2 NH-, -CH 2 NHCH 2- , -CH 2 CH 2 NH-, -CH 2 S-, -CH 2 SCH 2- , and -CH 2 CH 2 S-.
• heteroalkylene may also be optionally substituted with one or more substituents Q as described herein.
• alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon- carbon double bond(s).
• the alkenyl may be optionally substituted with one or more substituents Q as described herein.
• the term“alkenyl” also embraces radicals having cis and Ira ns configurations, or alternatively,“Z” and“E” configurations, as appreciated by those of ordinary skill in the art.
• the term“alkenyl” encompasses both linear and branched alkenyl, unless otherwise specified.
• C 2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
• the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C 2-20 ), 2 to 15 (C 2 _i 5 ), 2 to 10 (C 2 _io), or 2 to 6 (C 2-6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C 3-20 ),
• alkenyl groups include, but are not limited to, ethenyl, propen-l-yl, propen-2 -yl, allyl, butenyl, and 4-methylbutenyl.
• alkenylene refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon- carbon double bond(s).
• the alkenylene may be optionally substituted with one or more substituents Q as described herein.
• the term“alkenylene” also embraces radicals having“cis” and Ira ns configurations, or alternatively,“E” and“Z” configurations.
• the term“alkenylene” encompasses both linear and branched alkenylene, unless otherwise specified.
• C 2-6 alkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
• the alkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C 2-20 ), 2 to 15 (C 2 _i 5 ), 2 to 10 (C 2 _i 0 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3-i5 ), 3 to 10 (C 3-i0 ), or 3 to 6 (C 3-6 ) carbon atoms.
• alkenylene groups include, but are not limited to, ethenylene, allylene, propenylene, butenylene, and 4-methylbutenylene.
• heteroalkenylene refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon-carbon double bond(s), and which contains one or more heteroatoms each independently selected from O, S, and N in the hydrocarbon chain.
• the heteroalkenylene may be optionally substituted with one or more substituents Q as described herein.
• the term“heteroalkenylene” embraces radicals having a“cis” or“ trans” configuration or a mixture thereof, or alternatively, a“Z” or“E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art.
• C 2-6 heteroalkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
• the heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C 2-20 ), 2 to 15 (C 2 _i 5 ), 2 to 10 (C 2 _i 0 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3 _i 5 ), 3 to 10 (C 3-i0 ), or 3 to 6 (C 3-6 ) carbon atoms.
• alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon- carbon triple bond(s).
• the alkynyl may be optionally substituted with one or more substituents Q as described herein.
• the term“alkynyl” also encompasses both linear and branched alkynyl, unless otherwise specified.
• the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C 2-20 ), 2 to 15 (C 2 _i 5 ), 2 to 10 (C 2 _i 0 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3 _i 5 ), 3 to 10 (C 3 _i 0 ), or 3 to 6 (C 3-6 ) carbon atoms.
• alkynyl groups include, but are not limited to, ethynyl (-CoCH) and propargyl (- CH 2 CoCH).
• ethynyl -CoCH
• propargyl - CH 2 CoCH
• C 2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
• cycloalkyl refers to a cyclic saturated bridged and/or non-bridged monovalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein.
• the cycloalkyl has from 3 to 20 (C 3-20 ), from 3 to 15 (C 3 _i 5 ), from 3 to 10 (C 3 _io), or from 3 to 7 (C 3-7 ) carbon atoms.
• Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2. l . l]hexyl, bicyclo[2.2. l]heptyl, decalinyl, and adamantyl.
• cycloalkenyl refers to a cyclic unsaturated, nonaromatic bridged and/or non-bridged monovalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein.
• the cycloalkenyl has from 3 to 20 (C 3-20 ), from 3 to 15 (C 3 _i 5 ), from 3 to 10 (C 3 _i 0 ), or from 3 to 7 (C 3-7 ) carbon atoms.
• Examples of cycloalkyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl,
• aryl refers to a monocyclic aromatic group and/or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring.
• the aryl has from 6 to 20 (C 6-20 ), from 6 to 15 (C 6 _i 5 ), or from 6 to 10 (C 6 _i 0 ) ring atoms.
• aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
• Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).
• aryl may be optionally substituted with one or more substituents Q as described herein.
• aralkyl or“arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups.
• the aralkyl has from 7 to 30 (C 7-30 ), from 7 to 20 (C 7-20 ), or from 7 to 16 (C 7 _i 6 ) carbon atoms.
• Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenylethyl, and 3-phenylpropyl.
• the aralkyl are optionally substituted with one or more substituents Q as described herein.
• heteroaryl refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, N, and P in the ring.
• a heteroaryl group is bonded to the rest of a molecule through its aromatic ring.
• Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, one to four N atoms, and/or one or two P atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
• the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
• monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
• bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimi
• tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
• the heteroaryl may also be optionally substituted with one or more substituents Q as described herein as described herein.
• heterocyclyl refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, N, and P; and the remaining ring atoms are carbon atoms.
• the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
• a heterocyclyl group is bonded to the rest of a molecule through its non-aromatic ring.
• the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be spiro, fused, or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quatemized, and some rings may be partially or fully saturated, or aromatic.
• the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl,
• dihydropyrazinyl dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, l,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,
• heterocyclyl may also be optionally substituted with one or more substituents Q as described herein.
• halogen refers to fluorine, chlorine, bromine, and/or iodine.
• each R a , R b , R c , and R d is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heteroaryl or heterocyclyl, optionally substitute
• each substituent Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; and (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)R e , -C(0)0R e , -C(0)NR f R g , -C(NR e )NR f R g , -OR e , - R g , - f , R g , and R h is independently (i) hydrogen, Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aral
• “optically active” and’’enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
• the compound comprises about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer based on the total weight of the racemate in question.
• R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
• the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
• the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
• (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
• sign of optical rotation, (+) and (-) is not related to the absolute configuration of the molecule, R and S.
• phrases“an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof’ has the same meaning as the phrase“an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant of the compound referenced therein; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant of the compound referenced therein.”
• solvate refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which present in a stoichiometric or non-stoichiometric amount.
• Suitable solvents include, but are not limited to, water, methanol, ethanol, «-propanol, isopropanol, and acetic acid.
• the solvent is pharmaceutically acceptable.
• the complex or aggregate is in a crystalline form.
• the complex or aggregate is in a noncrystalline form.
• the solvent is water
• the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
• refractory can refer to a cancer for which treatment (e.g., chemotherapy drugs, biological agents, and/or radiation therapy) has proven to be ineffective.
• a refractory cancer tumor may shrink, but not to the point where the treatment is determined to be effective. Typically however, the tumor stays the same size as it was before treatment (stable disease), or it grows (progressive disease).
• the terms“intermittent dosing schedule” or“IS” refer to drugs (e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof) dosed or administered less than once daily.
• drugs e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof
• IS refers to dosing or administration of a drug (e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof), to a subject once daily for a period of about 7 days in a 28-day cycle.
• a drug e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof
• IS refers to dosing or administration of a drug (e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof) daily for up to three (e.g., two) 28-day cycles and, in the third cycle and subsequent cycles, dosing or administration of the drug to the subject once daily for a period of about 7 days in a 28-day cycle.
• a drug e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof
• a drug e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers
• the terms“continuous dosing schedule” or“CS” refer to drugs (e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof) dosed or administered once daily.
• drugs e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof
• CS refers to dosing or administration of a drug (e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof), to a subject daily in a 28-day cycle.
• a drug e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof
• CS refers to dosing or administration of a drug (e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof) daily for > three 28-day cycles and, in the one or more subsequent cycles, the drug is dosed or administered to the subject once daily for a period of about 7 days in a 28-day cycle (i.e., late switch to IS).
• the subject on CS is never switched to IS.
• CS is continued until intolerable toxicity occurs/is observed.
• a subject having CLL can be determined to be in complete remission (CR) or partial remission (PR).
• CR complete remission
• PR partial remission
• a subject is considered to be in CR if at least all of the following criteria as assessed after completion of therapy are met: (i) Peripheral blood lymphocytes (evaluated by blood and different count) below 4 x l0 9 /L (4000 pi); (ii) no hepatomegaly or splenomegaly by physical examination; (iii) absence of constitutional symptoms; and (iv) blood counts (e.g., neutrophils, platelets, hemoglobin) above the values set forth in Hallek, M. et al.
• Partial remission (PR) for CLL is defined according to IWCLL 2008 as including one of: (i) a decrease in number of blood lymphocytes by 50% or more from the value before therapy; (ii) a reduction in lymphadenopathy, as detected by CT scan or palpation; or (iii) a reduction in pretreatment enlargement of spleen or liver by 50% or more, as detected by CT scan or palpation; and blood counts (e.g., neutrophils, platelets, hemoglobin) according to the values set forth in Hallek, M. et al.
• CLL is determined to have progressive disease (PD) or stable disease (SD).
• PD progressive disease
• SD stable disease
• a subject is considered to be in PD during therapy or after therapy if at least one of the following criteria is met: (i) progression on lymphadenopathy; (ii) an increase in pretreatment enlargement of spleen or liver by 50% or more, or de novo appearance of hepatomegaly or splenomegaly; (iii) an increase in the number of blood lymphocytes by 50% or more with at least 5000 B lymphocytes per microliter; (iv) transformation to a more aggressive histology (e.g., Richter syndrome); or (v) occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) attributable to CLL.
• Stable disease (SD) for CLL is defined according to IWCLL 2008 as a patient who has not achieved CR or a PR, and who has not exhibited progressive disease.
• a subject with CLL responds to treatment with a PI3K inhibitor, alone or in combination, if at least one of the criteria for disease progression according to
• IWCLL is retarded or reduced, e.g., by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more
• a subject responds to treatment with a PI3K inhibitor, alone or in combination, if the subject experiences a life expectancy extension, e.g., extended by about 5%, 10%, 20%, 30%, 40%, 50% or more beyond the life expectancy predicted if no treatment is administered.
• a subject responds to treatment with a PI3K inhibitor, alone or in combination, if the subject has one or more of: an increased progression-free survival, overall survival or increased time to progression (TTP), e.g., as described in Hallek, M. et al.
• PI3K inhibitors useful for treating B cell malignanices.
• the PI3K inhibitor is selective for PI3K delta.
• X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are
• R x is hydrogen or Ci_ 6 alkyl
• R 1 and R 2 are each independently (a) hydrogen, cyano, halo, or nitro
• Ci_ 6 alkyl, C 24 alkenyl, C 24 , alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl
• -C(0)R la , -
• each R la , R lb , R lc , and R ld is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R lb and R lc together with the N atom to which they are attached form heterocyclyl;
• R 3 and R 4 are each independently hydrogen or Ci_ 6 alkyl; or R 3 and R 4 are linked together to form a bond, Ci- 6 alkylene, Ci_ 6 heteroalkylene, C 2-6 alkenylene, or
• R 5a is (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6-i4 aryl, C 7 _i 5
• R 5b is (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl,
• R 5C is -(CR 5f R 5g ) n -(C 6-14 aryl) or -(CR 5f R 5g ) n -heteroaryl;
• R 5d and R 5e are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
• R 5f and R 5g are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
• R 6 is hydrogen, Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -S(0)-Ci_ 6 alkyl, or -S0 2 -Ci_ 6 alkyl;
• n 0 or 1 ;
• n 0, 1, 2, 3, or 4;
• each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R 1 , R 2 , R 3 , R 4 , R 6 , R x , R la , R lb , R lc , R ld , R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , and R 5g is optionally substituted with one, two, three, four, or five substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5
• R c , and R d is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _ i4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one, two, three, or four substituents Q a ;
• each Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)R e , -C(0)0R e , -C(0)NR f R g , -C(NR e )NR f R g , -OR e , -0C(0)R e , -
• each R e , R f , R g , and R h is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are atached form heterocyclyl;
• the compound of structural Formula (I) is not 4-(2-(difluoromethyl)- l//- benzo[r/]imidazol-l-yl)-6-morpholino-/V-(2 -phenyl -2-(pyrrolidin-l-yl)ethyl)-l, 3, 5-triazin-2 -amine or 6-(2- (difluoromcthyl)- 1 //-bcnzo
• X, Y, and Z are each independently N or CR X with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R x is hydrogen or Ci_ 6 alkyl.
• R x is hydrogen or Ci_ 6 alkyl.
• X, Y, and Z are N.
• R 5b is (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, or heteroaryl; or (c)
• R 5a and R 5b are each independently (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2 _ e alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -
• R 5a and R 5b are each methyl, optionally substituted with one or more halo.
• R 5f and R 5g are each hydrogen.
• X, Y, and Z are each N;
• R 1 and R 2 are each hydrogen
• R 3 and R 4 are each hydrogen
• R 5a is C 1-6 alkyl
• R 5b is C 1-6 alkyl
• R 5C is -(CH 2 )-phenyl, wherein R 5c is optionally substituted with one, two, three, or four substituents Q;
• R 5d and R 5e are each hydrogen
• R 6 is CHF 2 ;
• n 0;
• each alkyl is optionally substituted with one, two, three, or four substituents Q, wherein each substituent Q is independently selected from C 6 _i 4 aryl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a , wherein the heteroaryl has from 5 to 10 ring atoms and one or more heteroatoms independently selected from O, S, and N, and the heterocyclyl has from 3 to 15 ring atoms and one or more heteroatoms independently selected from O, S, and N;
• each Q a is independently selected from the group consisting of halo, Ci_ 6 alkyl, Ci_ 6 alkylsulfonyl and -OR e , wherein R e is hydrogen or Ci_ 6 alkyl.
• X, Y, and Z are each N;
• R 1 and R 2 are each hydrogen
• R 3 and R 4 are each hydrogen
• R 5a and R 5b are each methyl, optionally substituted with one or more halo;
• R 5C is -(CH 2 )-phenyl, wherein R 5c is optionally substituted with one, two, three, or four substituents Q;
• R 5d and R 5e are each hydrogen
• R 6 is CHF 2 ;
• n 0;
• each alkyl is optionally substituted with one, two, three, or four substituents Q, wherein each substituent Q is independently selected from C 6 _i 4 aryl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a , wherein the heteroaryl has from 5 to 10 ring atoms and one or more heteroatoms independently selected from O, S, and N, and the heterocyclyl has from 3 to 15 ring atoms and one or more heteroatoms independently selected from O, S, and N;
• each Q a is independently selected from the group consisting of halo, Ci_ 6 alkyl, Ci_ 6 alkylsulfonyl and -OR e , wherein R e is hydrogen or Ci_ 6 alkyl.
• R 5C is C 6 _i4 aryl, optionally substituted with one or more substituents Q.
• R 5c is phenyl, optionally substituted with one or more substituents Q.
• R 5c is naphthyl, optionally substituted with one or more substituents Q.
• R 5c is -(CR 5f R 5g ) n -(C 6 _i 4 aryl), wherein the aryl is optionally substituted with one or more substituents Q.
• R 5C is -(CH 2 )-phenyl, wherein the phenyl is optionally substituted with one or more substituents Q.
• R 5c is -(CH 2 )-naphthyl, wherein the naphthyl is optionally substituted with one or more substituents Q.
• R 5c is heteroaryl, optionally substituted with one or more substituents Q.
• R 5c is monocyclic heteroaryl, optionally substituted with one or more substituents Q.
• R 5c is 5- or 6-membered heteroaryl, optionally substituted with one or more substituents Q.
• R 5c is bicyclic heteroaryl, optionally substituted with one or more substituents Q.
• R 5c is -(CR 5f R 5g ) n -heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents Q.
• R 5c is - (CR 5f R 5g ) n -(monocyclic heteroaryl), wherein the heteroaryl is optionally substituted with one or more substituents Q.
• R 5c is -(CR 5f R 5g ) n -(5- or 6-membered heteroaryl), wherein the heteroaryl is optionally substituted with one or more substituents Q.
• R 5c is -(CR 5f R 5g ) n -(bicyclic heteroaryl), wherein the heteroaryl is optionally substituted with one or more substituents Q.
• R 7c , R 7d , and R 7e are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ 6 alkyl, C 2-f alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) -C(0)R la , -C(0)0R la , -
• R 7a , R 7b , R 7c , R 7d , and R 7e that are adjacent to each other form C 3 _i 0 cycloalkenyl, C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.
• Formula (IX) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,
• R 7c , R 7d , and R 7e are each independently (a) hydrogen, cyano, halo, or nitro;
• R 7a is hydrogen, halo, Ci_ 6 alkyl optionally substituted with one or more substituents Q, or -OR la .
• R 7a is hydrogen. In some embodiments, R 7a is (a) cyano, halo, or nitro; (b) Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) -C(0)R la , -C(0)OR la , -
• R 7a is (i) halo; (ii) Ci_ 6 alkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -OR la or -NR lb R lc .
• R 7b is hydrogen, halo, Ci_ 6 alkyl optionally substituted with one or more substituents Q, or -OR la .
• R 71 ’ is hydrogen.
• R 7c is hydrogen, halo, Ci_ 6 alkyl optionally substituted with one or more substituents Q, or -OR la . In some embodiments, R 7c is hydrogen, halo, or -OR la . In some embodiments, R 7C is chloro. In some embodiments, R 7c is -0-Ci_ 6 alkyl, optionally substituted with one or more substituents Q.
• R 7d is hydrogen, halo, Ci_ 6 alkyl optionally substituted with one or more substituents Q, or -OR la . In some embodiments, R 7d is hydrogen.
• R 7e is hydrogen, halo, Ci_ 6 alkyl optionally substituted with one or more substituents Q, or -OR la .
• R 7e is hydrogen.
• R 7c , R 7d , and R 7e that are adjacent to each other form C 3 _i 0 cycloalkenyl, C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.
• R 7a and R 7b together with the carbon atoms to which they are attached form C 6 _i 4 aryl, optionally substituted with one or more substituents Q.
• R 5a is hydrogen. In some embodiments, R 5a is Ci_ 6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 5a is hydrogen, methyl, or ethyl.
• R 5b is Ci_ 6 alkyl, optionally substituted with one or more substituents Q.
• R 5b is methyl, ethyl, or propyl.
• R 5b is -C(0)OR la .
• R 5b is -C(0)0-Ci_ 6 alkyl.
• R 5b is -C(0)OCH 3 .
• Formula (X) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• R a , R 713 , R 7c , R d , and R 7e are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ; or (c) -C(0)R a , - R b R c , -C(NR a )NR b R c , -OR a , -0C(0)R a , -0C(0)0R a , -0C(0)NR b R c , - -0S(0)R a , -0S(0) 2 R a , -0S(0)NR b
• R 7d , and R 7e that are adjacent to each other form C 3 _i 0 cycloalkenyl, C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one, two, three, or four substituents Q a .
• one of R 7a , R 7 ' 1 . R 7c , R 7d , and R 7e is C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, one of R 7a , R 7b , R 7c , R 7d , and R 7e is C 6 _i 4 aryl, e.g., phenyl, optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, one of R 7a , R 7b , R 7c , R 7d , and R 7e is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, one of R 7a , R 71 ’.
• R 7c , R 7d , and R 7e is heterocyclyl, e.g., 5- membered or 6-membered heterocyclyl, optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, one of R 7a , R 71 ’.
• R 7c , R 7d , and R 7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, one of R 7a , R 7b , R 7c , R 7d , and R 7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q a ; in certain embodiments, one of R 7a , R 71 ’.
• R 7c , R 7d , and R 7e is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- methylpyridin-4-yl, 2-methoxypyridin-4-yl, l-methylpiperidin-4-yl, or 4-methylpiperazin-l-yl; and in certain embodiments, one of R 7a , R 7b , R 7c
• R 7a is C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, R 7a is C 6 _i 4 aryl, e.g., phenyl, optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, R 7a is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, R 7a is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, R a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl
• R 1 is hydrogen or -OR la , where R la is Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
• R 2 is hydrogen
• R 3 and R 4 are hydrogen
• R 6 is Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
• R 5a and R 5b are each independently Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
• R 5f and R 5g are each independently hydrogen, halo, Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q; or R 5f and R 5g together with the carbon atom to which they are attached form Ci_i 0 cycloalkyl or heterocyclyl, each of which is optionally substituted with one, two, three, four, or five substituents Q;
• R a is C 6 _i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
• R 7 * 1 , R 7c , R 7d , and R 7e are hydrogen
• X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are N; where R x is a hydrogen or Ci_ 6 alkyl, optionally substituted with one, two, three, or four substituents
• R 1 is hydrogen or methoxy
• R 2 is hydrogen
• R 3 and R 4 are hydrogen
• R 6 is Ci- 6 alkyl, optionally substituted with one or more halo
• R 5a and R 5b are each independently Ci_ 6 alkyl;
• R 5f and R 5g are each independently hydrogen or Ci_ 6 alkyl; or R 5f and R 5g together with the carbon atom to which they are attached form Cn 0 cycloalkyl;
• R a is C 6 _i aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
• R 7c , R 7d , and R 7e are hydrogen
• X, Y, and Z are each independently N or CH.
• R 1 is hydrogen or methoxy
• R 2 is hydrogen
• R 3 and R 4 are hydrogen
• R 6 is difluoromethyl
• R 5a and R 5b are methyl
• R 5f and R 5g are hydrogen; or R 5f and R 5g together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
• R a is C 6 _i aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
• R 715 , R 7c , R 7d , and R 7e are hydrogen
• X, Y, and Z are each independently N or CH.
• R 1 is hydrogen or methoxy
• R 2 is hydrogen
• R 3 and R 4 are hydrogen
• R 6 is difluoromethyl
• R 5a and R 5b are methyl
• R 5f and R 5g are hydrogen; or R 5f and R 5g together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
• R a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
• R 715 , R 7c , R 7d , and R 7e are hydrogen
• X, Y, and Z are each independently N or CH.
• R 1 is hydrogen or methoxy
• R 2 is hydrogen
• R 3 and R 4 are hydrogen
• R 6 is difluoromethyl
• R 5a and R 5b are methyl
• R 5f and R 5g are hydrogen; or R 5f and R 5g together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
• R a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
• R 7c , R 7d , and R 7e are hydrogen
• X, Y, and Z are each independently N or CH.
• R 7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q a .
• R 5a is Ci_ 6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 5a is methyl.
• R 5b is Ci_ 6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 5b is methyl.
• R 5a and R 5b are methyl.
• R 7a is hydrogen, halo, Ci_ 6 alkyl, C 6 _i 4 aryl, heteroaryl, or heterocyclyl, where the alkyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted with one or more substituents Q.
• R 7a is C 6 _i 4 aryl, optionally substituted with one or more substituents Q.
• R 7a is phenyl, optionally substituted with one or more substituents Q
• R 7a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,
• R 7a is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In some embodiments, R 7a is imidazolyl, pyrozolyl, pyridinyl, or pyrimidinyl, each optionally substituted with one or more substituents Q.
• R 7a is imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2- yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-l- yl)pyridin-4-yl,
• R 7a is heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is 5- or 6-membered heterocyclyl, each optionally substituted with one or more substituents Q. In some embodiments, R 7a is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q.
• R 7a is pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, 1- ethylpiperidin-4-yl,
• R 7b is hydrogen, halo, or Ci_ 6 alkyl optionally substituted with one or more substituents Q. In some embodiments, R 7b is hydrogen.
• R 7c is hydrogen, halo, or Ci_ 6 alkyl optionally substituted with one or more substituents Q. In some embodiments, R 7c is hydrogen.
• R 7d is hydrogen, halo, or Ci_ 6 alkyl optionally substituted with one or more substituents Q. In some embodiments, R 7d is hydrogen.
• R 7e is hydrogen, halo, or Ci_ 6 alkyl optionally substituted with one or more substituents Q. In some embodiments, R 7e is hydrogen.
• R 7a is C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; and R 7b , R 7c , R 7d , and R 7e are hydrogen.
• one of R 7a , R b . R 7c , R 7d , and R 7e is C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , the remaining of R 7a , R 7b , R 7c , R 7d , and R 7e , X, Y, and Z are each as defined herein.
• one of R 7a , R 7b , R 7c , R 7d , and R 7e is C 6 _i 4 aryl, which is optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 ,
• R 5b the remaining of R 7a , R 715 , R 7c , R 7d , and R 7e , X, Y, and Z are each as defined herein.
• one of R 7a , R 715 , R 7c , R 7d , and R 7e is heteroaryl, which is optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , the remaining of R 7a , R 7b , R 7c , R 7d , and R 7e , X, Y, and Z are each as defined herein.
• one of R 7a , R 715 , R 7c , R 7d , and R 7e is heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , the remaining of R 7a , R 7b , R 7c , R 7d , and R 7e , X, Y, and Z are each as defined herein.
• one of R 7a , R 715 , R 7c , R 7d , and R 7e is
• one of R 7a , R 715 , R 7c , R 7d , and R 7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , the remaining of R 7a , R 7b , R 7c , R 7d , and R 7e , X, Y, and Z are each as defined herein.
• one of R 7a , R 715 , R 7c , R 7d , and R 7e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3- dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4- ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, 1
• one of R 7a , R 715 , R 7c , R 7d , and R 7e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- methoxyphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, l-methylpiperidin-4-yl, or 4- methylpiperazin
• R 7a is C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R a .
• R 5b , R 7b , R 7c , R 7d , R 7e , X, Y, and Z are each as defined herein.
• R 7a is heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , R 7b ,
• R 7c , R 7d , R 7e , X, Y, and Z are each as defined herein.
• R 7a is 5-membered or 6-membered heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , R b , R 7c , R d , R 7e , X, Y, and Z are each as defined herein.
• R 7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , R 7b , R 7c , R 7d , R 7e , X, Y, and Z are each as defined herein.
• R 7a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl - pyrozol-4-yl, 2-methylpyrozol-3-yl, pyr
• R 7a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- methylpyridin-4-yl, 2-methoxypyridin-4-yl, l-methylpiperidin-4-yl, or 4-methylpiperazin-l-yl; and R 1 ,
• R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , R b , R 7c , R 7d , R 7e , X, Y, and Z are each as defined herein.
• R 1 is hydrogen or -OR la , where R la is Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
• R 2 is hydrogen
• R 3 and R 4 are hydrogen
• R 6 is Ci- 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
• R 5a and R 5b are each independently Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
• R a is C 6 _i aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ;
• R 715 , R 7c , R 7d , and R 7e are hydrogen.
• R 1 is hydrogen or methoxy
• R 2 is hydrogen
• R 3 and R 4 are hydrogen
• R 6 is Ci_ 6 alkyl, optionally substituted with one or more halo
• R 5a and R 5b are each independently Ci_ 6 alkyl
• R a is C 6 _i aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
• R 715 , R 7c , R 7d , and R 7e are hydrogen.
• R 1 is hydrogen or methoxy
• R 2 is hydrogen
• R 3 and R 4 are hydrogen
• R 6 is difluoromethyl
• R 5a and R 5b are methyl
• R a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, four, or five substituents Q; and
• R 715 , R 7c , R 7d , and R 7e are hydrogen.
• R 5a and R 5b are each independently (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or
• R lb , R lc , and R ld are defined herein elsewhere.
• R 1 is hydrogen or -OR la , where R la is Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
• R 2 is hydrogen
• R 3 and R 4 are hydrogen
• R 6 is Ci- 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
• R 5a and R 5b are each independently hydrogen or Ci_ 6 alkyl optionally substituted with one, two, three, four, or five substituents Q;
• R a is C 6 _i aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
• R 715 , R 7c , R 7d , and R 7e are hydrogen
• X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are N; where R x is a hydrogen or Ci_ 6 alkyl, optionally substituted with one, two, three, or four substituents
• R 1 is hydrogen or methoxy
• R 2 is hydrogen
• R 3 and R 4 are hydrogen
• R 6 is Ci_ 6 alkyl, optionally substituted with one or more halo
• R 5a and R 5b are each independently hydrogen or Ci_ 6 alkyl
• R a is C 6 _i aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
• R 715 , R 7c , R 7d , and R 7e are hydrogen
• X, Y, and Z are each independently N or CH.
• R 1 is hydrogen or methoxy
• R 2 is hydrogen
• R 3 and R 4 are hydrogen
• R 6 is difluoromethyl
• R 5a and R 5b are each independently hydrogen or Ci_ 6 alkyl;
• R a is C 6 _i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
• R 7c , R 7d , and R 7e are hydrogen
• X, Y, and Z are each independently N or CH.
• R 1 is hydrogen or methoxy
• R 2 is hydrogen
• R 3 and R 4 are hydrogen
• R 6 is difluoromethyl
• R 5a and R 5b are each independently hydrogen or Ci_ 6 alkyl
• R a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
• R 715 , R 7c , R 7d , and R 7e are hydrogen
• X, Y, and Z are each independently N or CH.
• R 1 is hydrogen or methoxy
• R 2 is hydrogen
• R 3 and R 4 are hydrogen
• R 6 is difluoromethyl
• R 5a and R 5b are each independently hydrogen or Ci_ 6 alkyl
• R a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
• R 715 , R 7c , R 7d , and R 7e are hydrogen
• X, Y, and Z are each independently N or CH.
• R 1 is hydrogen or methoxy
• R 2 is hydrogen
• R 3 and R 4 are hydrogen
• R 6 is difluoromethyl
• R 5a and R 5b are each independently hydrogen or Ci_ 6 alkyl
• R a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
• R 715 , R 7c , R 7d , and R 7e are hydrogen
• X, Y, and Z are each independently N or CH.
• R 1 is hydrogen. In one embodiment of any of the formulae provided herein, R 1 is -OR la . In one embodiment of any of the formulae provided herein, R 1 is -0-Ci_ 6 alkyl. In one embodiment of any of the formulae provided herein, R 1 is methoxy.
• R 2 is hydrogen. In one embodiment of any of the formulae provided herein, R 2 is -NR lb R lc . In one embodiment of any of the formulae provided herein, R 2 is amino.
• R 3 is hydrogen
• R 4 is hydrogen
• R 6 is Ci_ 6 alkyl, optionally substituted with one or more substituents Q.
• R 6 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl. In one embodiment of any of the formulae provided herein, R 6 is difluoromethyl.
• n is 0. In certain embodiments, m is 1.
• n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 0, 1, 2, or 3. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is 1 or 2.
• m is 0, and n is 0, 1, 2, or 3. In certain embodiments, m is 0, n is 0, 1, or 2. In certain embodiments, m is 0, n is 0 or 1. In certain embodiments, m is 0, n is 0. In certain embodiments, m is 0 and n is 1. In certain embodiments, m is 1, n is 0, 1, 2, or 3. In certain embodiments, m is 1, n is 0, 1, or 2. In certain embodiments, m is 1, n is 0 or 1. In certain embodiments, m is 1, n is 0. In certain embodiments, m is 1, n is 1.
• n is 1
• R 5a and R 5b are each methyl.
• X is N. In certain embodiments, X is CR X , wherein R x is as defined herein. In certain embodiments, X is CH.
• Y is N. In certain embodiments, Y is CR X , wherein R x is as defined herein. In certain embodiments, Y is CH.
• Z is N. In certain embodiments, Z is CR X , wherein R x is as defined herein. In certain embodiments, Z is CH.
• X, Y, and Z are N. In certain embodiments, X and Y are N, and Z is CH. In certain embodiments, X and Z are N, and Y is CH. In certain embodiments, Y and Z are N, and X is CH.
• the compound provided herein is not 4-(2-(difluoromethyl)- l//- benzo[r/]imidazol-l-yl)-6-morpholino-/V-(2 -phenyl -2-(pyrrolidin-l-yl)ethyl)-l, 3, 5-triazin-2 -amine.
• the compound provided herein is not 6-(2-(difluoromethyl)- l//-benzo
• R 5a is hydrogen
• R 5b is not heterocyclyl.
• R 5a is hydrogen
• R 5b is not 5-membered heterocyclyl.
• R 5b when X, Y, and Z are N, and R 5a is hydrogen, R 5b is not pyrrolidinyl. In certain embodiments, when X, Y, and Z are N, and R 5a is hydrogen, R 5b is not pyrrolidin-l-yl.
• R 5a is hydrogen
• R 5b is morpholino- substituted phenyl.
• R 5a is hydrogen
• R 5b is not 4-((R)-3 -(methoxymethyl)morpholino)phenyl .
• the PI3K inhibitor is Compound A35, or an isotopic variant
• the PI3K inhibitor is Compound A36, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the PI3K inhibitor is Compound A68, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the PI3K inhibitor is Compound A70, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the PI3K inhibitor is Compound A37, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the PI3K inhibitor is Compound A38, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the PI3K inhibitor is Compound A41, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the PI3K inhibitor is Compound A42, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the PI3K inhibitor is Compound A43, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the PI3K inhibitor is Compound A44, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is Compound A62, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is Compound A63, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is Compound A64, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the PI3K inhibitor is Compound A65, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is Compound A66, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is Compound A67, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• Some embodiments provided herein describe a method for treating a patient with B cell maligancies, the method comprising administering to the patient in need thereof an effective amount of a PI3K inhibitor having the structure of Formula (I). Also provided herein, in some embodiments, is a method of preventing relapse in a patient with B cell maligancies, the method comprising administering the patient in need thereof with an effective amount of a PI3K inhibitor having the structure of of Formula (I). In some embodiments provided herein is a method for achieving and retaining partial cancer remission in a patient with B cell maligancies, the method comprising administering to the patient in need thereof an effective amount of a PI3K inhibitor having the structure of Formula (I). In some embodiments provided herein is a method for achieving and retaining complete cancer remission in a patient with B cell maligancies, the method comprising administering to the patient in need thereof an effective amount of a PI3K inhibitor of Formula (I).
• the methods, including dosing regimens and schedules, described herein avoid or reduce adverse or unwanted side effects associated with the use of a PI3K inhibitor.
• the methods described herein avoid, reduce, or minimize the risk of death due to infections.
• the methods described herein avoid, reduce, or minimize infections, neutropenia, diarrhea/colitis, elevated liver transaminases (alanine aminotransferase/aspartate aminotransferase > 5x upper limit of normal), pneumonitis, rash, hepatic impairment, renal impairment, pyrexia, or increased triglycerides, or a combination thereof in patients receiving the treatment described herein.
• the methods described herein avoid, reduce, or minimize the incidence of infection. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of neutropenia. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of diarrhea/colitis. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of elevated liver transaminases. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of pneumonitis. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of a rash. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of hepatic impairment or renal impairment. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of pyrexia.
• the methods described herein avoid, reduce, or minimize the incidence of increased triglycerides. In certain embodiments, the methods described herein avoid, reduce, or minimize enterocolitis (manifested as diarrhea), cutaneous toxicities, liver toxicity (manifested as elevation of transaminases), pulmonary toxicity (manifested as non-infectious pneumonitis), infections, or combinations thereof.
• the methods described herein provides a high objective response rate (ORR) as determined by tumor assessment from radiological tests and/or physical examination.
• ORR high objective response rate
• the methods described herein provide a durable response (DR) and/or increased durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12 months of treatment and lasting >6 months) in the subject or patient.
• the methods described herein provide complete remission.
• the methods described herein provide complete remission beginning within 12 months of treatment and lasting >6 months.
• the methods described herein provide a complete response (CR) and/or no evidence of disease (NED) beginning within 12 months of treatment and lasting >6 months.
• the discontinuation rate due to adverse events is less than 25%, less than 20%, less than 15%, less than 10%, less than 8%, less than 5%.
• The“discontinuation rate” is defined as the number of subjects who discontinue the study drugs prior to the study completion divided by the number of subjects treated.
• the discontinuation rate due to adverse events is less than 25%, less than 20%, less than 15%, less than 10%, less than 8%, less than 5%. In some embodiments, the discontinuation rate due to adverse events is less than 25%. In some embodiments, the discontinuation rate due to adverse events is less than 20%. In some embodiments, the discontinuation rate due to adverse events is less than 15%. In some embodiments, the discontinuation rate due to adverse events is less than 10%. In some embodiments, the discontinuation rate due to adverse events is less than 8%. In some embodiments, the discontinuation rate due to adverse events is about 4%.
• the discontinuation rate due to adverse events when the subjects are administered a compound of Formula (I), or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is less for subjects on an intermittent dosing schedule (IS) than the discontinuation rate observed for subjects on a continuous dosing schedule (CS).
• IS intermittent dosing schedule
• CS continuous dosing schedule
• provided herein are methods for treating or preventing a disease comprising administering an effective amount of a compound of Formula (I), or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.
• the compound of Formula (I) is Compound A35 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the compound of Formula (I) is Compound A36 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the compound of Formula (I) is Compound A68 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments of the methods provided herein, the compound of Formula (I) is Compound A70 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments of the methods provided herein, the compound of Formula (I) is Compound A37 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments of the methods provided herein, the compound of Formula (I) is Compound A38 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the compound of Formula (I) is Compound A41 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the compound of Formula (I) is Compound A42 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the compound of Formula (I) is Compound A43 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the compound of Formula (I) is Compound A44 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the compound of Formula (I) is Compound A62 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments of the methods provided herein, the compound of Formula (I) is Compound A63 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments of the methods provided herein, the compound of Formula (I) is Compound A64 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments of the methods provided herein, the compound of Formula (I) is Compound A65 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the compound of Formula (I) is Compound A66 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments of the methods provided herein, the compound of Formula (I) is Compound A67 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the B cell malignancy is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), high-risk chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s
• macroglobulinemia multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitts lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B- cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
• PMBL primary mediastinal B- cell lymphoma
• immunoblastic large cell lymphoma precursor B -lymphoblastic lymphoma
• B cell prolymphocytic leukemia lymphoplasmacy
• the B cell malignancy is selected from non-Hodgkin's lymphoma, Burkitf s lymphoma, small lymphocytic lymphoma, primary effusion lymphoma, diffuse large B-cell lymphoma, splenic marginal zone lymphoma, MALT (mucosa-associated lymphoid tissue) lymphoma, hairy cell leukemia, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B cell lymphomas (e.g. various forms of Hodgkin's disease, B cell non-Hodgkin's lymphoma (NHL), leukemias (e.g.
• the B cell malignancy is diffuse large B-cell lymphoma (DLBCL). In certain embodiments, the B cell malignancy is diffuse large B-cell lymphoma (DLBCL).
• the DLBCL is an activated B-cell DLBCL (ABC-DLBCL), a germinal center B-cell like DLBCL (GBC-DLBCL), a double hit DLBCL (DH-DLBCL), or a triple hit DLBCL (TH-DLBCL).
• the B cell malignancy is B-cell non-Hodgkin’s lymphoma (NHL).
• the B-cell malignancy is selected from chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), marginal zone B cell lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), and high grade non -Hodgkin's lymphoma.
• CLL chronic lymphocytic leukemia
• SLL small lymphocytic lymphoma
• FL follicular lymphoma
• MZL marginal zone B cell lymphoma
• DLBCL diffuse large B-cell lymphoma
• high grade non -Hodgkin's lymphoma high grade non -Hodgkin's lymphoma.
• the B-cell malignancy is selected from chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), marginal zone B cell lymphoma (MZL), or diffuse large B-cell lymphoma (DLBCL).
• the B cell malignancy is a relapsed or refractory B cell malignancy.
• the FL is a relapsed or refractory FL (R/R FL).
• the FL is relapsed/refractory FL after failure of at least two prior lines of systemic therapy in the subject.
• the FL is relapsed/refractory FL after failure of at least two prior lines of systemic therapy in the subject, wherein the systemic therapy comprises an anti-CD20 antibody and/or chemotherapy with an alkylating agent or a purine analog.
• follicular lymphoma FL
• methods of treating follicular lymphoma (FL) in a subject in need thereof, wherein the subject has failed two or more prior chemotherapies In some embodiments provided herein are methods of treating follicular lymphoma (FL) in a subject in need thereof, wherein the subject has failed two or more prior systemic chemotherapies. In some embodiments provided herein are methods of treating follicular lymphoma (FL) in a subject in need thereof, wherein the subject has failed two or more prior systemic chemotherapies, wherein each systemic chemotherapy is selected from the group consisting of an anti-CD20 antibody, an alkylating chemotherapeutic agent, and a chemotherapeutic purine analog.
• kits comprising administering to a subject in need thereof a single pharmaceutical composition consisting of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate as monotherapy.
• a method of treating follicular lymphoma (FL) comprising administering to a subject in need thereof a therapeutically effective amount of a single pharmaceutical composition consisting of:
• Some embodiments provided herein describe a method of treating relapsed follicular lymphoma (FL), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate as monotherapy.
• a method of treating relapsed follicular lymphoma comprising administering to a subject in need thereof a therapeutically effective amount of a single pharmaceutical composition consisting of: (i) compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate; and (ii) one or more pharmaceutically acceptable carriers.
• the methods provided herein comprise administering a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof to a patient in need thereof.
• the method for multiple cycle chemotherapy comprises the administration of a second cycle within about 60 days or about 3 months. In some instances, the method for multiple cycle chemotherapy comprises the administration of a second cycle within 50 days. In another instance, the second cycle is administered within 45, 40, 35, 30, 25, 21, 20, 15, 14, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 day(s) of the first cycle. In some embodiments, the administration of any additional cycles is within 50 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 10 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 9 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 8 days of the previous cycle.
• the administration of any additional cycles is within 7 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 6 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 5 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 4 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 3 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 2 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 1 day of the previous cycle. In another embodiment, the additional cycle is administered within 45, 40, 35, 30, 25, 21, 20, 15, 14, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 days of the previous cycle.
• the length of a treatment cycle depends on the treatment being given. In some embodiments, the length of a treatment cycle ranges from two to six weeks. In some embodiments, the length of a treatment cycle ranges from four to six weeks. In some embodiments, the length of a treatment cycle is 28 days. In some embodiments, the length of a treatment cycle is 56 days. In some embodiments, a treatment cycle lasts one, two, three, or four weeks. In some embodiments, a treatment cycle lasts four weeks. The number of treatment doses scheduled within each cycle also varies depending on the drugs being given.
• the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject on a 28-day cycle.
• the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for at least one 28-day cycle.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered daily to the subject on a 28-day continuous schedule until disease progression or intolerable toxicity.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for a period of up to about 7 days.
• the days over which the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof are intermittent.
• administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for about 7 consecutive days in a 28-day cycle.
• the method comprises an intermittent dosing schedule (IS), comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for 7 consecutive days followed by 21 days without treatment in a 28-day cycle.
• IS intermittent dosing schedule
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject for at least one 28-day cycle.
• the IS avoids or reduces adverse or unwanted side effects associated with the use of the PI3K inhibitor, such as enterocolitis (manifested as diarrhea), cutaneous toxicities, liver toxicity (manifested as elevation of transaminases), pulmonary toxicity (manifested as non-infectious pneumonitis), and infections.
• the IS avoids or reduces enterocolitis, rash, transaminitis, or combinations thereof.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject once daily for 28 consecutive days in a 28-day cycle.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject on continuous dosing schedule (CS).
• CS continuous dosing schedule
• the continuous dosing schedule comprises once daily administration of compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof to the subject for 28 consecutive days in a 28-day cycle.
• compound of Formula (I) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof to the subject for 28 consecutive days in a 28-day cycle.
• the continuous dosing schedule comprises once daily administration of compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof to the subject for 28 consecutive days in a 28-day cycle until disease progression or intolerable toxicity.
• CS continuous dosing schedule
• patients on CS report of delayed onset of cases of enterocolitis and rash.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject once daily for a period of up to about 7 days in a 28-day cycle.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject once daily for a period of up to about 7 intermittent days in a 28-day cycle.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject once daily for a period of up to about 7 consecutive days in a 28-day cycle.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject once daily for a period of up to about 7 consecutive days in a 28-day cycle.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject once daily for a period of 7 consecutive days in a 28-day cycle.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject on an intermittent dosing schedule (IS).
• IS intermittent dosing schedule
• the intermittent dosing schedule comprises once daily administration of compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof to the subject for 7 consecutive days followed by 21 days without treatment in a 28-day cycle.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for at least three 28-day cycles, wherein: the first two 28-day cycles comprise a continuous daily dosing schedule (CS), comprising administering to the subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, once daily for two 28- day cycles; and the third28-day cyclecomprises an intermittent dosing schedule (IS), comprising administering to the subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture
• IS intermittent dosing schedule
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for at least three cycles, wherein: the first two cycles comprise a continuous daily dosing schedule (CS), comprising administering to the subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for two cycles; and the subsequent cycle(s) comprises an intermittent dosing schedule (IS), comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for four or more 28-day cycles, wherein: the first two or three 28-day cycles comprise a continuous daily dosing schedule (CS), comprising administering to the subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, once daily for three or more 28-day cycles; and the subsequent 28-day cycle(s) comprise(s) an intermittent dosing schedule (IS), comprising administering to the subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers
• CS refers to continuous daily dosing to a subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily on a 28-day schedule with no switch to IS.
• CS refers to continuous daily dosing to a subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily on a 28-day schedule for four or more cycles followed by a switch to IS (i.e., late switch to IS).
• pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a subject on an intermittent dosing schedule (IS) until progression of disease.
• IS intermittent dosing schedule
• the subject upon progression of disease, resumes continuous daily dosing (CS) of the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the treatment regimen comprising administration of the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for two cycles of continuous daily administration (CS) followed by daily administration for only the first seven days of each subsequent cycle, the CS and IS cycles are 28-day cycles.
• CS continuous daily administration
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject on an intermittent dosing schedule (IS) to reduce or mitigate adverse side effects associated with PI3K5 inhibitors (e.g., enterocolitis, rash, and/or transaminitis).
• IS intermittent dosing schedule
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject on an intermittent dosing schedule (IS) resulting in mitigation or reduction of the incidence of immune -mediated toxicities by allowing recovery of TREG during treatment-free intervals.
• IS intermittent dosing schedule
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject on an intermittent dosing schedule (IS) resulting in disease stabilization.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject on an intermittent dosing schedule (IS) resulting in disease regression.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject on an intermittent dosing schedule (IS) resulting in an objective rseponse.
• IS intermittent dosing schedule
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject on an intermittent dosing schedule (IS) until disease stabilization is no longer observed.
• the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject on an intermittent dosing schedule (IS) until disease progression is observed.
• the treatment regimen comprising administration of the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for two cycles of continuous daily administration (CS) followed by daily administration for only the first seven days of each subsequent (IS) cycle, the CS and IS cycles are 28-day cycles, wherein the IS cycle is repeated until disease regression is no longer observed.
• the subject resumes the 28-day cycles of continuous daily administration (CS) until disease regression or stabilization are observed
• the treatment regimen comprising administration of the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for two 28-day cycles of continuous daily administration (CS) followed by daily administration for only the first seven days of each subsequent (IS) 28-day cycle; wherein disease regression or stabilization is no longer observed in the subject on the intermittent dosing schedule (IS) cycle, the subject resumes 28-day cycles of continuous daily administration (CS) until disease regression or stabilization are observed.
• CS continuous daily administration
• pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject once daily for a period of 7 consecutive days in a 28-day cycle followed by 21 days without therapy, with cycles repeated every 28 days.
• administration of about 60 mg of the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a subject in need thereof once daily for a period of 7 consecutive days followed by 21 days without treatment in a 28-day cycle results in steady-state plasma concentrations sufficient to inhibit PI3K5 in target malignant B-cells.
• the subsequent 21 days without treatment is sufficient to repopulate TREG (i.e., 7 days to clear the compound of Formula (I) from the plasma ( ⁇ 7 half-lives) and 14 days for reconstitution of TREG after the compound of Formula (I) is cleared from the plasma.
• the method comprises a continuous daily dosing schedule (CS) for at least two CS 28-day cycles, followed by an intermittant dosing schedule (IS), comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for 7 consecutive days followed by 21 days without treatment in a 28-day cycle after the at least two CS 28-day cycles.
• CS continuous daily dosing schedule
• IS intermittant dosing schedule
• the dosing schedule avoids or reduces adverse or unwanted side effects associated with the use of the PI3K inhibitor, such as enterocolitis (manifested as diarrhea), cutaneous toxicities, liver toxicity (manifested as elevation of transaminases), pulmonary toxicity (manifested as non-infectious pneumonitis), and infections.
• the dosing schedule avoids or reduces enterocolitis, rash, transaminitis, or combinations thereof.
• the method for the administration of multiple compounds comprises administering compounds within 48 hours or less of each other. In some embodiments administration occurs within 24 hours, 12 hours, 6 hours, 3 hours, 1 hour, or 15 minutes. In some instances, the compounds are administered simultaneously.
• simultaneous administration is the injection of one compound immediately before, after, or during the oral administration of the second compound, immediately referring to a time less than about 5 minutes.
• the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 30, about 60 mg, about 120 mg, about 150 mg, or about 180 mg. In certain embodiments, the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 60 mg. In certain embodiments, the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 30 mg/day.
• the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 45 mg/day. In certain embodiments, the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 60 mg/day. In certain embodiments, the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 90 mg/day.
• the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 120 mg/day. In certain embodiments, the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 150 mg/day. In certain embodiments, the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 180 mg/day.
• the pharmaceutical compositions provided herein can be formulated in the form of tablets containing from about 1.0 to about 1,000 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in one embodiment, about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 50, about 60, about 75, about 100, about 120, about 150, about 180, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, and about 1,000 mg of the a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for the symptomatic adjustment of the dosage to the patient to be treated.
• the pharmaceutical compositions provided herein can be formulated in the form of tablets containing about 30 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 30 mg daily for 28 days or 56 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 30 mg daily for 28 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 30 mg daily for 56 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 30 mg daily until disease progression or intolerable toxicity.
• the pharmaceutical compositions provided herein can be formulated in the form of tablets containing about 45 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 45 mg daily for 28 days or 56 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 45 mg daily for 28 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 45 mg daily for 56 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 45 mg daily until disease progression or intolerable toxicity.
• the pharmaceutical compositions provided herein can be formulated in the form of tablets containing about 60 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 60 mg daily for 28 days or 56 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 60 mg daily for 28 days. In other specific embodiments, a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 60 mg daily for 56 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 60 mg daily until disease progression or intolerable toxicity.
• the pharmaceutical compositions provided herein can be formulated in the form of tablets containing about 90 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 90 mg daily for 28 days or 56 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 90 mg daily for 28 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 90 mg daily for 56 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 90 mg daily until disease progression or intolerable toxicity.
• the pharmaceutical compositions provided herein can be formulated in the form of tablets containing about 120 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 120 mg daily for 28 days or 56 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 120 mg daily for 28 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 120 mg daily for 56 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 120 mg daily until disease progression or intolerable toxicity.
• the pharmaceutical compositions provided herein can be formulated in the form of tablets containing about 150 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 150 mg daily for 28 days or 56 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 150 mg daily for 28 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 150 mg daily for 56 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 150 mg daily until disease progression or intolerable toxicity.
• the pharmaceutical compositions provided herein can be formulated in the form of tablets containing about 180 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 180 mg daily for 28 days or 56 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 180 mg daily for 28 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 180 mg daily for 56 days.
• a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 180 mg daily until disease progression or intolerable toxicity.
• the compounds provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g.. U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.
• packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
• kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject.
• the kit provided herein includes one or more containers and a dosage form of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• the kit provided herein includes one or more containers and a dosage form of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
• Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle-less injectors drip bags, patches, and inhalers.
• Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
• the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate -free sterile solution that is suitable for parenteral administration.
• Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
• aqueous vehicles including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection
• water-miscible vehicles including, but not limited to,
• Example 1 In some instances, severe cases of enterocolitis, rash, and transaminitis have been reported in a Phase lb clinical study of Compound A35 in patients with B-cell malignancies. In some instances, the onset of severe immune-related toxicities were reported after a period of CS dosing greater than 2 cycles. A lymphocytic infiltrate was reported in biopsies obtained from 1 patient with colitis and 1 patient with severe skin rash enrolled in the study. Furthermore, corticosteroid therapy has been reported as effective treatment approach in patients who developed diarrhea and rash in the study.
• PI3K5 inhibitors including Compound A35 could reduce the incidence or lower the severity of immune mediated adverse events (irAEs) by allowing recovery of TREGs during treatment-free intervals.
• the IS by delivering a lower dose-intensity treatment approach, could be used to re-treat patients who have experienced delayed irAEs on the CS or IS and had recovered following treatment interruption and a short course of corticosteroids.
• TREGs repopulation occurs approximately 14 days after the administration of a single dose of the anti-CD25 immunotoxin denileukin diftitox (ONTAK®), a drug known to suppress TREGs. Therefore, it was hypothesized that
• Intermittent Dosing Schedule demonstrates improved tolerability compared to continuous dosing schedule.
• an intermittent dosing schedule on days 1-7 of a 28-day cycle was then evaluated after 2 cycles of daily dosing, or >3 cycles of daily dosing to reduce the risk of immune-related adverse events.
• the intermittent schedule (IS) group is defined as patients who received Compound A35 alone or with rituximab daily for 2 cycles then switched to an intermittent schedule of 1 week per cycle
• the continous schedule (CS) group is defined as patients who never switched to intermittent dosing or switched to intermittent dosing in cycle 4 or later cycles.
• Toxicity on CS is managed by a switch to IS.
• Progression of disease on IS is managed by a switch to CS.
• Group A 31 patients enrolled in a dose escalation phase of the study, with Compound A35
• Group A Monotherapy on the CS with Later Switch to the IS
• the IS was developed to mitigate the risk of delayed toxicities observed with PI3K inhibitors and believed to be associated with on-target effect PI3K inhibition on immune cells.
• the incidence of severe adverse events of special interest (AESI) associated with PI3K inhibition was substantially reduced with the IS dosign compared to the CS dosing (Tables 4 and 5).
• Example 3 Phase 2 Study of Compound A35 in Subjects with Follicular Lymphoma after Failure of Two or More Prior Systemic Therapies
• Compound A35 is provided as a capsule, taken orally.
• Group A Continuous schedule. Compound A35 is administered daily continuously. Compound A35 is a capsule, taken orally once a day (60 mg/day).
• Group B Intermittent schedule. Compound A35 is administered daily continuously for 2 cycles then daily for the first 7 days of each subsequent cycle.
• ORR of Compound A35 in relapsed Follicular Lymphoma defined as the best response rating of complete response (CR) or partial response (PR) according to the Lugano Response Criteria (Cheson 2014), as determined by an Independent Response Review Committee (IRRC)

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• 2019
  • 2019-08-13 AU AU2019321432A patent/AU2019321432A1/en not_active Abandoned
  • 2019-08-13 JP JP2021506716A patent/JP2021534115A/ja active Pending
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  • 2019-08-13 US US17/268,052 patent/US20210299134A1/en not_active Abandoned
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